CRF antagonists are drugs which can counter the deleterious effects associated with high levels of CRF through receptor blockade. For both CRF and CRF binding sites a wide distribution in the central and peripheral nervous system has been described. Increasing data substantiate that CRF is involved in the brain and periphery in coordinating endocrine, behavioral, autonomic and immune responses to stress and recent clinical data implicate CRF in the etiology and pathophysiology of a variety of endocrine, psychiatric and neurodegenerative disorders [Dietrich et al., Corticotropin-releasing factor receptors: An overview, Exp.Clin. Endocrinol.Diabetes 105: 65-82 (1997)]. It is thus anticipated that CRF-antagonists play a beneficial role in normalizing pathophysiological states associated with high CRF-levels.
Several peptide CRF-antagonists including .alpha.-helical CRF.sub.9-41 have been disclosed e.g. in Rivier et al., Synthetic competitive antagonists of corticotropin-releasing factor: effect on ACTH secretion in the rat, Science 224: 889-891 (1984), and more recently non-peptide CRF recptor antagonists were disclosed e.g. in Chen et al., Design and synthesis of a series of non-peptide high-affinity human corticotropin-releasing factor 1 receptor antagonists, J.Med.Chem. 39: 4358-4360 (1996), in Whitten et al., Rapid microscale synthesis, a new method for lead optimization using robotics and solution phase chemistry: application to the synthesis and optimization of corticotropin-releasing factor 1 receptor antagonists, J.Med.Chem. 39: 4354-4357 (1996) or in Chen et al., Synthesis and oral efficacy of a 4-(butylethylamino)pyrrolo[2,3-d]pyrimidine: a centrally active corticotropin-releasing factor 1 receptor antagonist, J.Med.Chem. 40(11) 1749-1754 (1997).
CRF-antagonists are proposed to be useful in the treatment of a variety of disorders associated with high levels of corticotropin-releasing factor, and inflammatory diseases such as arthritis, asthma and allergies, anxiety, depression, fatigue syndrome, headache, pain, cancer, irritable bowel syndrome, including Crohn's disease, spastic colon and irritable colon, immune dysfunction, HIV infections, neurodegenerative diseases such as senile dementia, gastrointestinal diseases, eating disorders such as anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction and fertility problems.